Diabetic polyneuropathy (DPN) is a complex, often insidious and multifactorial disease process. The value of animal models of DPN, including hyperglycemia induced by streptozocin (STZ) and genetic mutations, is largely determined by the sensitivity and validity of the surrogate endpoints utilized. Most animal models of DPN have relied heavily, if not exclusively, on changes in maximal nerve conduction velocity as an index of nerve "function." Although objective and reliable, maximal nerve conduction velocity is a highly selective measure, sensitive to only some elements of neural activity in only a limited subset of responding neurons (i.e. large diameter, heavily myelinated axons). Thus, in many current studies of DPN, decisions are being made about putative therapeutic agents and about correlations of structure, biochemistry and function using a principal measure (i.e. maximal conduction velocity) that is insensitive to several key aspects of neural activity. The studies outlined in this proposal are intended to develop and refine a new battery of electrophysiologic measures, which could serve as sensitive, objective, surrogate markers for the onset and progression of DPN. It is hypothesized that the development of these more comprehensive measures would significantly expand our ability to explore the pathogenesis of DPN, as well as improve our ability to distinguish the mechanism, time course and efficacy of new therapies. We will evaluate new electrophysiologic measures that reflect activity in medium and small diameter axons, register the spatial distributions of activity along distal-to-proximal gradients and are sensitive to refractory cycles and neural fatigue, which are in turn influenced by the underlying pattern of transmembrane energy utilization. Initial studies will examine the technical details and reliability of the new measures; later studies will examine the value of these measures in an STZ-induced model of DPN and the impact of various classes of putative therapeutic agents (i.e. ARls, neurotrophic factors, superoxide scavengers). The procedures explored will be non-invasive, whole nerve methods and will therefore be applicable to multiple laboratories and species, as well as translatable to electrophysiologic measures in human population studies and clinical trials.